Conclusions
Our study suggested eIF3a with a high potential to influence phenotypic functions, which may contribute substantially to the early identification of susceptible individuals and the provision of personalized medication to irinotecan-treated patients.
Methods
The cck8 cell viability and clone survival analyses were used to test the regulatory role of eIF3a on irinotecan sensitivity in HT29 and CACO2 cell lines in vitro. This regulatory role was also verified in vivo by conducting subcutaneous xenograft model. Irinotecan-induced DNA damage, cell cycle arrest and apoptosis were tested by flow cytometry analysis, TUNEL staining, western blot and comet assays. The immunofluorescence, co-IP, luciferase reporter assay, RIP and flow cytometric analyses were carried out to investigate the underline mechanism.
Results
We demonstrated that eIF3a continuously activates ATM/ATR signal by translationally inhibiting PPP2R5A, a phosphatase that directly dephosphorylates and inactivates ATM/ATR after DNA repair complete. Suppression of PPP2R5A resulted in chronic ATM/ATR phosphorylation and activation, impairing DNA repair and enhancing irinotecan sensitivity. Conclusions: Our study suggested eIF3a with a high potential to influence phenotypic functions, which may contribute substantially to the early identification of susceptible individuals and the provision of personalized medication to irinotecan-treated patients.